In recent years, with the repeated cloning of glutamate receptor genes, it has become clear that there are surprisingly many subtypes of glutamate receptors. At present, glutamate receptors are roughly classified into two types: the "ionotropic type", in which the receptor has an ion channel type structure, and the "metabotropic type", in which the receptor is coupled to G-proteins. Ionotropic receptors are classified pharmacologically into three types: N-methyl-D-asparaginic acid (NMDA), .alpha.-amino-3-hydroxy-5-methyl isoxazole-4-propionate (AMPA), and kynate (Science, 258, 597-603, 1992). Metabotropic receptors are classified into eight types, type 1 through type 8 (J. Neurosci., 13, 1372-1378, 1993; Neuropharmacol., 34, 1-26, 1995).
The metabotropic glutamate receptors are classified pharmacologically into three groups. Of these, group 2 (mGluR2/mGluR3) bind with adenylcyclase, and inhibit the accumulation of the Forskolin stimulation of cyclic adenosine momophosphate (cAMP) (Trends Pharmacol. Sci., 14, 13(1993)), which suggests that compounds that act on group 2 metabotropic glutamate receptors should be useful for the treatment or prevention of acute and chronic psychiatric and neurological diseases. As substances that act on group 2 metabotropic glutamate receptors, (+)-(1S,2S,5R,6S)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid has been disclosed in Japanese Unexamined Patent Publication, First Publication No. Hei 8-188561 [1996]. And, (1S*,2S*,5R*,6R*)-2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, (1S*,2S*,4S*,5R*,6R*)-2-amino-4-hydroxybicyclo[3.1. 0]hexane-2,6-dicarboxylic acid, and (1S*,2R*,4S*,5S*,6S*)-2-amino-4-flurobicyclo[3.1.0]hexane-2,6-dicarboxylic acid have been disclosed in EP-A-878,463.
Fluorine atoms tend to be strongly electron-attractive and to confer high fat solubility, so that compounds into which fluorine atoms are introduced greatly change their physical properties. Thus introducing fluorine atoms might greatly affect the absorbability, metabolic stability, and pharmacological effects of a compound. But it is by no means easy to introduce fluorine atoms. In fact, Japanese Unexamined Patent Publication, First Publication No. Hei 8-188561 [1996] does not even discuss the introduction of fluorine atoms into (+)-(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Further, (1S*,2R*,4S*,5S*,6S*)-2-amino-4-flurobicyclo[3.1.0]hexane-2,6-dicarboxylic acid which has been disclosed in EP-A-878,463 was prepared by merely a substitution of a hydroxyl group in (1S*,2S*,4S*,5R*,6R*)-2-amino-4-hydroxybicyclo[3.1. 0]hexane-2,6-dicarboxylic acid, by a fluorine atom by use of normal fluorination agents.